Through this research, we seek to identify the mechanism by which dysregulated TGF-beta signaling promotes atopy and discover how disordered glycosylation, and elevations in serum tryptase converge on a similar clinical phenotypes. We seek to identify and develop novel diagnostic and therapeutic targets for clinical allergic disease beyond rare monogenic disorders. Patients with Congenital Disorders of Glycosylation (CDGs), and other monogenic syndromes presenting with severe allergic disease in association with connective tissue abnormalities are actively being recruited and studied. A high throughput flow-based lectin binding assay to quantify N-glycan binding has been developed in order to study these patients; this is now being employed to screen syndromic populations for N-glycan defects. Using a TGF-beta reporter cell line, defects in discrete immune pathways and in glycosylation processes are under active investigation employing a number of techniques including cellular transfection and pathway inhibition with small molecules, siRNAs, and antibodies. A clinical protocol to provide patients with CDGs and evidence of immune dysregulation with monosaccharide and nucleoside supplementation is open for enrollment and currently recruiting patients. This protocol will provide novel insights into the role that alterations in glycosylation may play in atopy by characterizing how supplementation may alter immune responses.